WO2023025272A1 - Small-molecule drug sustained-release delivery system - Google Patents

Abstract

The present invention relates to a pharmaceutical composition, comprising a pharmaceutically active ingredient, glycerol, a sustained-release carrier, and a pharmaceutically acceptable solvent. The pharmaceutical composition is small in irritation, has good sustained-release performance, medication safety and tolerance, is high-viscosity liquid at normal temperature, and is particularly beneficial to perfusion administration.

Description

A slow-release drug delivery system for small molecule drugs

This application claims the priority of the prior application submitted by the applicant to the State Intellectual Property Office of China on August 27, 2021, with the patent application number 202110997613.7, and the invention titled "A Small Molecule Drug Sustained Release Delivery System". The entirety of this prior application is incorporated by reference into the present application.

technical field

The invention belongs to the field of pharmaceutical preparations, and in particular relates to a slow-release drug delivery system for small molecule drugs.

Background technique

Injectable sustained-release preparations are one of the current research hotspots of pharmaceutical preparations, which aim to provide a drug reservoir, which can be used for subcutaneous injection, intramuscular injection, intramuscular injection, local injection and other administration methods. Among them, local injection refers to local administration, such as injection in the spinal cavity, joint cavity, wound, eye, etc., and the drug can exert its effect locally after the drug is slowly released.

Injectable sustained-release preparations have many advantages, for example: the preparation can be directly injected into the desired administration site for slow drug release, reducing systemic toxicity and increasing therapeutic effect; secondly, the preparation can also reduce the number of administrations and improve patient compliance; In addition, the preparation can significantly reduce the cost of treatment. However, this type of preparation also has some disadvantages, for example: since the drug is released over a long period of time and usually cannot be withdrawn after administration, good preparation stability is required. In addition, it is necessary to pay attention to whether the sustained-release preparation will cause a burst release effect, or produce other adverse effects such as diffusion and toxicity at the injection site.

In recent years, research on sustained-release technology for injectables mainly includes oil sustained-release systems, polymer-based and lipid-based sustained-release systems, etc.

The oil sustained-release system is mainly based on injectable vegetable oil and organic solvents. Patent 201310022657.3 discloses an analgesic sustained-release drug delivery system composed of an analgesic, drug vehicle, and drug sustained-release agent. The drug sustained-release agent is liquid oil. Due to the low viscosity of the oil sustained-release system and the diffusion of organic solvents in the body, it may cause a burst release phenomenon, which has potential safety hazards. In addition, its release is relatively fast, which cannot meet the release requirements of some drugs.

Polymer sustained-release systems are mainly polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA) and polyorthoester (POE). Patent document US200303156A1 provides a slow-release microsphere composition and a preparation method thereof. The composition includes polymer PLGA, active substance risperidone or 9-hydroxyrisperidone and other excipients. In 2003, the FDA approved a long-acting risperidone microsphere developed by Janssen Pharmaceuticals with PLGA as the sustained-release carrier, and the trade name is RISPERDAL

The extended release microspheres provide sustained release for 14 days. Heron Therapeutics Inc disclosed in the patent document CN106535886A a polyorthoester as a slow-release carrier, a composition containing an amide local anesthetic, an enol non-steroidal anti-inflammatory drug and a polyorthoester and a preparation method thereof. Currently approved by the European Union under the trade name

Because polymer materials degrade slowly at the site of administration, there are safety risks.

Lipid-based sustained-release systems are mainly lipoplexes and liposomes. PACIRA has developed a long-acting bupivacaine multivesicular liposomal suspension injection with the trade name

It is used to treat postoperative pain and nerve block, and the analgesic effect can last for 24 hours. The liposome mainly contains two kinds of synthetic phospholipids, dierucoyl phosphatidylcholine (DEPC) and dipalmitoylphosphatidylglycerol (DPPG), and encapsulating bupivacaine in the multivesicular liposome can play a slow-release effect. However, the preparation process of multivesicular liposomes is complex and requires high storage conditions. In addition, the patent CN103705442 discloses an in-situ lipid gel preparation, which is characterized in that the preparation contains phospholipids, a therapeutically effective amount of active substances and a solvent; the phospholipids are preferably one of soybean lecithin, egg yolk lecithin or several, more preferably soybean lecithin; the solvent contains an organic solvent, preferably one or more of absolute ethanol, benzyl alcohol, tert-butanol, glycerin, and water or a physiological aqueous medium. Patent CN103705439 discloses a lipid gel preparation, which is characterized in that the preparation comprises PEGylated phospholipids, non-PEGylated phospholipids, therapeutically effective doses of active substances and solvents, in which water or Physiological aqueous medium acts as solvent and does not contain cholesterol. CN102933200 discloses a single-phase gel composition, which comprises: 20% to 80% by weight of one or more phospholipids; 0.1% to 70% by weight of water, wherein high shear, high energy or A high pressure homogenizer such that the phospholipids have a particle size of less than 100 nm and the gel composition can be passed through a 25G x 1/2 inch long needle and extruded from a 1 cc syringe at a rate of 2 cc/min with a force not exceeding 12 lbs. and said composition optionally further comprises a pharmacologically active agent. Patents CN103705442, CN103705439 and CN102933200 all contain water in different proportions, which may have stability problems such as easy oxidation and low viscosity, so they can only be administered by subcutaneous injection.

The sustained-release systems that have been approved or are currently under research have problems such as complex preparation process, difficult degradation of sustained-release carriers, and safety caused by burst release. In addition, the lipid-based sustained-release systems under research or on the market all have low viscosity and cannot meet the problem of incisional drug delivery. Therefore, there is an urgent need to develop a sustained-release preparation system suitable for pharmaceutical use, with improved stability, safety, tolerance and/or sustained-release performance, and high viscosity.

Contents of the invention

In order to improve the problems existing in the prior art, the present invention provides a liquid pharmaceutical composition, comprising the following components:

a. Pharmaceutical active ingredients;

b. Glycerin;

c. slow-release carrier, the slow-release carrier is selected from one or more of the compounds of formula I or formula II, and the compound of formula I is

Wherein, Rs is selected from H,

Each R ₁ , R ₂ is the same or different, independently selected from saturated or unsaturated aliphatic hydrocarbon groups; each R ₃ , R ₄ , R ₅ is the same or different, independently selected from H or alkyl; L is selected from Alkylene; The compound of formula II is

Wherein, R is selected from alkyl;

d. At least one pharmaceutically acceptable solvent.

According to an embodiment of the present invention, the pharmaceutical composition may further comprise a pharmaceutically acceptable release modifier.

According to an embodiment of the present invention, in the formula I, each R ₁ and R ₂ are the same or different, and are independently selected from C _10-30 saturated or unsaturated aliphatic hydrocarbon groups, such as C _13-21 alkyl groups; each R ₃ , R ₄ , and R ₅ are the same or different, and are independently selected from H or C _1-10 alkyl groups, such as independently selected from H, methyl, and ethyl; the L is selected from C _1-10 alkyl groups Alkyl, preferably, L is selected from C _1-6 alkylene, such as methylene, ethylene;

According to an embodiment of the present invention, in the compound represented by formula II, R is selected from C _1-10 alkyl groups, such as C _8-10 alkyl groups.

According to an embodiment of the present invention, the c-component slow-release carrier is selected from HSPC (hydrogenated soybean lecithin), DMPC (dimyristoyl phosphatidylcholine), DPPC (dipalmitoyl phosphatidylcholine), DSPC (di Stearoylphosphatidylcholine), DLPC (dilauroylphosphatidylcholine), SPC soybean phosphatidylcholine (soybean phosphatidylcholine), EPC (egg yolk phospholipid), rapeseed phosphatidylcholine, sunflower phosphatidylcholine, DEPC (dierucoyl egg phosphatidylcholine) Phospholipids), DOPC (Dioleoyl Lecithin), POPC (Palmitoyl Oleoyl Lecithin), Sphingomyelin, Distearoyl Phosphatidic Acid (DSPA), Dioleoyl Phosphatidylethanolamine (DOPE), Dipalmitoyl Phospholipid Acid (DPPA), myristoyl lysophospholipid (M-lysoPC), palmitoyl lysophospholipid (P-lysoPC), 1-stearyl-lysophosphatidylcholine (S-lysoPC), dipalmitoyl phosphatidylethanolamine ( DPPE), distearoylphosphatidylethanolamine (DSPE), dioleoylphosphatidylglycerol (DOPG), dimyristoylphosphatidylethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphospholipid Acylglycerol (DPPG), 1-palmitoyl-2-oleoylphosphatidylglycerol (POPG), distearoylphosphatidylglycerol (DSPG), dipalmitoylphosphatidylserine (DPPS), phosphatidylinositol ( PI), one or more of cholesterol (CHO).

Preferably, the c-component slow-release carrier is SPC soybean phosphatidylcholine (soybean lecithin), EPC (egg yolk phospholipid), DEPC (dierucoyl lecithin), DOPC (dioleacyl lecithin), POPC ( one or more of palmitoyl oleoyl lecithin).

According to an embodiment of the present invention, the pharmaceutically active ingredient is not limited to the type of treatment, and may be anti-inflammatory drugs, local anesthetics, analgesics, antipsychotics, anxiolytics, sedative-hypnotics, antidepressants, antihypertensives Blood pressure drugs, steroid hormones, antiepileptic drugs, bactericides, anticonvulsants, antiparkinsonian drugs, central nervous system stimulants, antipsychotics, antiarrhythmic drugs, antianginal drugs, antithyroid drugs, antidotes, antiemetics Drugs, hypoglycemic drugs, anti-tuberculosis drugs, anti-AIDS drugs, anti-hepatitis B drugs, anti-tumor drugs, anti-rejection drugs and their mixtures.

According to an embodiment of the present invention, suitable pharmaceutically active ingredients may be selected from one or more combinations of the following compounds: aspirin, acetaminophen, benoate, indomethacin, sulindac, diclofenac, Diclofenac potassium, diclofenac sodium, ibuprofen, naproxen, flurbiprofen, flurbiprofen axetil, loxoprofen, nabumetone, ketorolac, phenylbutazone, butadiene hydroxyacid, fenol Profen, Celecoxib, Rofecoxib, Polmacoxib, Nimesulide, Meloxicam, Lornoxicam, Piroxicam, Etodolac, Valdecoxib, Parecoxib, Erecoxib, Lu Micoxib. Bupivacaine, Levobupivacaine, Ropivacaine, Mepivacaine, Lidocaine, Procaine, Benzocaine, Tetracaine, Dyclonine. Enkephalins, dynorphins, beta-endorphins, naltrexone, buprenorphine, morphine, dimethylmorphine, codeine, dihydrocodeine, oxycodone, hydrocodone, nab Caffeine, Fentanyl, Sufentanil, Remifentanil, Tramadol, Nortramadol, Tapentadol, Dezocine, Pentazocine, Methadone, Pethidine, Ketamine, Diazepam Panam, Chlormetazepam, Lisdexamphetamine, Dextropropoxyphene, Difelikefalin, Oliceridine. Chlorpromazine, triflupromazine, mesoridazine, pecitazine, thioridazine, chlorprothixene. Diazepam, alprazolam, clonazepam, oxazepam, imipramine, amitriptyline, doxepin, nortriptyline, amoxapine, tranylcypromine, phenethyl Hydrazine. Procainamide, isoamyl nitrite, nitroglycerin, propranolol, metoprolol, prazosin, phentolamine, mithiophene, captopril, enalapril. Clonidine, dexmedetomidine, epinephrine, norepinephrine, tizanidine, alpha-methyldopa, glycopyrrolate. cortisone, hydrocortisone, betamethasone, triamcinolone acetonide, dexamethasone, dexamethasone ester, prednisone, prednisolone, methylprednisolone, beclomethasone, clobetasol, progesterone , Testosterone, Testosterone Enanthate, Testosterone Undecanoate, Testosterone Cypionate, Progesterone, Fulvestrant, Pregnenolone, Ganaxolone, Phenytoin, Ethytoin. Benzalkonium Chloride, Benzethonium Chloride, Sulfamethonium Acetate, Mebenzethonium Chloride, Furacilin, Mercury Nicresol. Phenobarbital, amobarbital, pentobarbital, secobarbital. carbidopa, levodopa, aniracetam, oxiracetam, piracetam, doxapram, aripiprazole, olanzapine, haloperidol, quetiapine, risperidone , clozapine, paliperidone, atenolol, bisoprolol, metoprolol. Atenolol, amlodipine, nimodipine, isosorbide mononitrate, epoprostenol, treprostinil, iloprost, beraprost. Methimazole, propylthiouracil, propranolol, naloxone, lofexidine, flumazenil, amphetamine. Granisetron, ondansetron, tropisetron, dolasetron, palonosetron, scopolamine, domperidone, glipizide, glibenclamide, glimepiride, glibenclamide, glibenclamide Zite, tolbutamide, liraglutide, exelatide, dulaglutide, semaglutide. Darunavir, dolutegravir sodium, emtricitabine, raltegravir, ritonavir, stavudine, nevirapine, zidovudine, stavudine, etravirine, adelaide Fovir dipivoxil, entecavir, telbivudine, lamivudine, tenofovir disoproxil, fosproxil, tenofovir, thiosemicarbazide, pyrazinamide, prothionamide, cyclophosphamide, 5-fluorouracil, carmustine, lomustine, melphalan, chlorambucil, methotrexate, vincristine, bleomycin, doxorubicin, tamoxifen, cyclosporine, other Crolimus, everolimus, sirolimus and pharmaceutically acceptable salts, stereoisomers and derivatives of said compounds.

According to an embodiment of the present invention, the pharmaceutically active ingredient is selected from amide local anesthetics, for example, from bupivacaine, ropivacaine, levobupivacaine, mepivacaine, and lidocaine in salt form. The salt of the amide local anesthetic may be selected from fatty acid salts and water-soluble salts thereof, and the acids forming the salt include lauric acid, myristic acid, stearic acid, palmitic acid, behenic acid, arachidic acid, methanesulfonic acid, Hydrochloric acid, sulfonic acid, phosphoric acid, acetic acid, citric acid, maleic acid, etc.

According to an embodiment of the present invention, the pharmaceutically active ingredient further includes a second active ingredient in addition to an amide local anesthetic, and the pharmaceutically active ingredient can be selected from COX receptor inhibitors, adrenergic receptor agonists, and sugars. One of the corticosteroid drugs. The COX receptor inhibitors include non-selective COX inhibitors and selective COX-2 inhibitors. NSAIDs represented in these classes include, but are not limited to, the following non-selective COX inhibitors: aspirin, acetaminophen, benolate, indomethacin, sulindac, diclofenac, diclofenac potassium, Diclofenac sodium, ibuprofen, naproxen, flurbiprofen, loxoprofen, nabumetone, piroxicam, ketorolac, phenylbutazone, butyrate, fenoprofen; the following optional COX-2 inhibitors: celecoxib, rofecoxib, nimesulide, meloxicam, lornoxicam, etodolac, valdecoxib, parecoxib, erecoxib, lumixide cloth. As well as pharmaceutically acceptable salts, stereoisomers, and derivatives of said compounds. The adrenergic receptor agonists are mainly α2-adrenoceptor agonists, including but not limited to clonidine, dexmedetomidine, epinephrine, norepinephrine, tizanidine, α-methyl doba. The glucocorticoid drugs include, but are not limited to cortisone, hydrocortisone, betamethasone, triamcinolone acetonide, dexamethasone, prednisone, prednisolone, methylprednisolone, beclomethasone , Clobetasol.

In some embodiments, the pharmaceutical active ingredient is selected from ropivacaine hydrochloride, ropivacaine mesylate, bupivacaine hydrochloride, levobupivacaine hydrochloride, meloxicam, celecoxib, One or a combination of ketorolac and triamcinolone acetonide.

In some embodiments, the pharmaceutically active ingredient is selected from a combination of an amide local anesthetic and a non-steroidal anti-inflammatory drug, such as a combination of ropivacaine hydrochloride and meloxicam, levobupivacaine hydrochloride and meloxicam Composition, bupivacaine hydrochloride and meloxicam composition, ropivacaine mesylate and meloxicam composition, ropivacaine mesylate and celecoxib composition, ropivacaine hydrochloride and Celecoxib composition, levobupivacaine hydrochloride and celecoxib composition, bupivacaine hydrochloride and celecoxib composition, etc. According to an embodiment of the present invention, the pharmaceutically acceptable release regulator is selected from one or more of sterols, saturated phospholipids and other surfactants. The saturated phospholipid is used to adjust the viscosity of the sustained-release drug delivery system, thereby adjusting the drug diffusion rate, and the sterol and surfactant are used to adjust the hydrophilicity of the sustained-release drug delivery system, so as to achieve the desired drug release rate.

In some embodiments, the sterol comprises cholesterol.

In some embodiments, the saturated phospholipids include hydrogenated soybean phospholipids (HSPC), dilauroyl lecithin (DLPC), dimyristoyl lecithin (DMPC), distearoyl phosphatidylcholine (DSPC), di Palmitoyl lecithin, etc. (DPPC), etc.

In some embodiments, the surfactant is a nonionic surfactant. In some embodiments, the surfactant includes polyoxyl 40 stearate, macrogol glyceride caprylate, lauroyl polyoxyethylene glyceride, stearoyl polyoxyethylene glyceride, oleoyl Polyoxyethylene Glycerides, Vitamin E Polyethylene Glycol Succinate, Poloxamer, Polysorbate, Macrogol-12-Hydroxystearate, Propylene Glycol Monocaprylate, Glyceryl Dioleate, Glyceryl monooleate, etc. The poloxamer can be selected from, for example, poloxamer 407, poloxamer 188, and the polysorbate can be selected from, for example, polysorbate 80.

According to an embodiment of the present invention, the composition may further comprise one or more antioxidants. Antioxidants can be used to prevent or reduce oxidation of phospholipids in the sustained release drug delivery system of the present invention. Antioxidants provided by the present invention include but are not limited to vitamin C (ascorbic acid), cysteine hydrochloride, vitamin E (tocopherol), ascorbyl palmitate, glutathione, alpha lipoic acid, thioglycerol.

According to an embodiment of the present invention, the composition may further include other conventional excipients in the field of pharmacy. Examples of suitable pharmaceutical excipients are in Excipients and their use in injectable products. PDA J Pharm Sci Technol. Volume 51 , July-August 1997, pp. 166-171 and described in Excipient Selection In Parenteral Formulation Development, Pharma Times, Vol. 45, No. 3, March 2013, pp. 65-77, which are cited in their entirety and into the present invention.

According to an embodiment of the present invention, the mass ratio of the glycerol to the slow-release carrier/pharmaceutically acceptable solvent is 1:0.1 to 1:99, such as 1:0.1, 1:0.5, 1:1, 1:5, 1 :10, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1:65, 1:70 , 1:75, 1:80, 1:85, 1:90, 1:95, 1:99. In some embodiments, the mass ratio of glycerin to sustained-release carrier/pharmaceutically acceptable solvent is 1:0.3 to 1:35. In some embodiments, the mass ratio of glycerin to sustained-release carrier/pharmaceutically acceptable solvent is 1:1 to 1:19.

According to an embodiment of the present invention, the mass ratio of the slow-release carrier to the pharmaceutically acceptable solvent is 1:0.1 to 1:10, such as 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5 , 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1 :9, 1:10. In some embodiments, the mass ratio of the slow-release carrier to the pharmaceutically acceptable solvent is 1:0.3 to 1:8. In some embodiments, the mass ratio of the slow-release carrier to the pharmaceutically acceptable solvent is 1:0.7 to 1:8.

According to an embodiment of the present invention, the glycerol accounts for about 1% to about 95% (w/w) of the total composition, such as about 1%, 2%, 3%, 4%, 5%, 6%, 7% %, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40% , 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57 %, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90% , 91%, 92%, 93%, 94%, 95%. In some embodiments, the proportion of glycerol is about 2% to 60% (w/w). In some embodiments, the proportion of glycerol is about 3% to 30% (w/w).

According to an embodiment of the present invention, the slow-release carrier accounts for 3% to 90% (w/w) of the total composition, such as 3%, 4%, 5%, 6%, 7%, 8%, 9% , 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26 %, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59% , 60%, 61%, 62%, 63%, 64%, 64%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76 %, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%. In some embodiments, the sustained release carrier comprises 20% to 60% (w/w) of the total composition.

According to an embodiment of the present invention, the pharmaceutically active ingredient accounts for 0.1% to 50.0% (w/w) of the total composition. According to some embodiments, the pharmaceutically active ingredient accounts for 0.1% to 15% (w/w) of the total composition, such as 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%, 11.0%, 11.5%, 12.0% , 12.5%, 13.0%, 13.5%, 14.0%, 14.5%, 15.0%. According to some embodiments, the pharmaceutically active ingredient is present in an amount of 3% (w/w) to 10% (w/w). According to some embodiments, when the pharmaceutically active ingredient is selected from two or more, each pharmaceutically active ingredient can account for 0.1% to 15% (w/w) of the total composition, such as 0.1%, 0.5%, 1.0%, 1.5% %, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%, 11.0%, 11.5%, 12.0%, 12.5%, 13.0%, 13.5%, 14.0%, 14.5%, 15.0%.

According to an embodiment of the present invention, the total amount of the pharmaceutically acceptable solvent accounts for 5% to 50% (w/w) of the total amount of the composition. In some embodiments, the total amount of the pharmaceutically acceptable solvent Can account for 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% of the total composition %, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%. In some embodiments, the total amount of the pharmaceutically acceptable solvent accounts for 10%-50% (w/w) of the total composition, and in some embodiments, the total amount of the pharmaceutically acceptable solvent accounts for From 5% to 30% (w/w) of the total composition.

According to an embodiment of the present invention, the pharmaceutically acceptable solvent is a non-aqueous solvent, and the non-aqueous solvent is selected from ethanol, N-methylpyrrolidone, benzyl alcohol, n-propanol, isopropanol, n-butanol, One or more combinations of isobutanol and tert-butanol.

According to an embodiment of the present invention, the release modifier accounts for 0% to 40% (w/w) of the total composition, preferably 0.1% to 40% (w/w). In some embodiments, The release modifier can account for 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4% of the total composition , 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21 %, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, in some embodiments, when the release modifier is selected from saturated phospholipids, the amount of the release modifier is 1 to 30% (w/w); in some embodiments, When the release modifier is selected from surfactants, the release modifier is used in an amount of 0.1% to 5% (w/w).

According to an embodiment of the present invention, the pharmaceutical composition provided by the present invention is a high-viscosity liquid preparation. The viscosity of the liquid preparation is ≥ 500 mPa·s at normal temperature (about 25°C). In some embodiments, the composition has a viscosity of 500 to 100,000 mPa·s at 25°C. In some embodiments, the composition has a viscosity in the range of 500 to 50000 mPa·s at 25°C. In some embodiments, the viscosity of the composition is in the range of 500 to 30000 mPa·s at 25°C. In some embodiments, the viscosity of the composition is in the range of 500 to 15000 mPa·s at 25°C. In some embodiments, the viscosity of the composition is in the range of 500 to 10000 mPa·s at 25°C.

In the pharmaceutical composition of the present invention, the pharmaceutically acceptable solvent and release modifier can act as a viscosity modifier to make the composition suitable for injection. The present invention provides a kind of preparation method of described pharmaceutical composition, comprises the steps:

(a1) Mix the slow-release carrier and the pharmaceutically acceptable solvent, stir or shear under heating conditions to a clear and uniform mixed solution;

(a2) adding at least one pharmaceutically active ingredient to the mixed solution, stirring or shearing under heating conditions to form a homogeneous mixture;

(a3) Adding glycerin to the mixed solution, stirring or shearing under heating conditions until a uniform solution is formed.

According to an embodiment of the present invention, the mixing of the step (a1) also includes adding at least one pharmaceutically acceptable release regulator, for example, the step (a1) can be slow-release carrier, pharmaceutically acceptable Solvent, glycerol and release modifier are mixed.

In some embodiments, the method includes:

1. Mix the slow-release carrier, pharmaceutically acceptable solvent, pharmaceutically acceptable active ingredient, and glycerin at 50-70°C until a clear and transparent solution is obtained.

2. Pass the hot solution through a 0.22μm membrane filter to sterilize.

3. Cool the filtered mixed solution to room temperature.

The present invention provides a sustained release formulation comprising said pharmaceutical composition, said formulation being administered as a depot formulation, in one aspect said formulation being injectable. In another aspect, the formulation can be administered topically.

In another aspect, the formulation may be administered subcutaneously, perineurally, intramuscularly, or by infusion (direct application into a wound, arterial infusion, rectal infusion).

In another aspect, the formulation is suitable for topical dermal or mucosal administration.

The preparation provided by the invention is administered in a single dose, and the amount of the medicine contained therein can achieve the effects of analgesia and nerve block, and can be used for preventing or alleviating local pain.

According to some embodiments, the preparation provided by the present invention can form a stable reservoir at the site of administration, which can release the drug slowly and continuously, prolong the release time of the drug, and improve the therapeutic effect.

In some embodiments, the formulation is effective for at least 24 hours after administration. In some embodiments, the formulation is effective for at least 24 to 48 hours after administration. In some embodiments, the formulation is effective for at least 48 to 72 hours after administration. In some embodiments, the formulation is effective for at least 72 hours after administration. According to an embodiment of the present invention, the preparation further includes a packaging material filled with the preparation, and the packaging material is selected from one or more of the following: vials, prefilled syringes, and cartridges.

Terms and Abbreviations

Unless otherwise stated, the definitions of groups and terms recorded in the specification and claims of this application include their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples etc., can be arbitrarily combined and combined with each other. Such combinations and combined group definitions and compound structures should fall within the scope of the description of the present application.

For the numerical ranges described in the specification and claims of this application, when the numerical range is defined or it can only be an "integer", it should be understood as describing the two endpoints of the range and every integer in the range. For example, "an integer of 0 to 10" should be understood as describing every integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.

When the numerical range is defined as a "number" or may include "integer" or "non-integer", it should be understood that both endpoints of the range, each integer within the range, and each integer within the range are recited. decimal. For example, "the number from 0 to 10" should be understood as not only recording each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least recording each of the integers respectively Sum with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.

The term "aliphatic group" includes saturated or unsaturated, linear or branched chain-like hydrocarbon group, the type of said aliphatic group can be selected from alkyl (saturated aliphatic group), unsaturated aliphatic group (containing at least one double bond and /or triple bond, such as alkenyl, alkynyl) etc., the number of carbon atoms of the aliphatic hydrocarbon group is preferably 1-40, further preferably 1-30 (such as C1, C2, C3, C4, C5, C6, C6 , C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30), Specifically, it may include but not limited to the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl , vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 1-ethylvinyl, 1-methyl-2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 1-hexenyl, ethynyl, 1-propynyl, 2-propenyl Alkynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl and 1-hexynyl; the "aliphatic hydrocarbon group" part contained in other groups is the same as explained above.

The term "alkyl" is a saturated aliphatic hydrocarbon group, which conforms to the relevant definition in the above-mentioned aliphatic hydrocarbon group. For example, the number of carbon atoms in the alkyl group is preferably 1-40, more preferably 1-30, or 1-10 (such as C1, C2, C3, C4, C5, C6, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35, C36, C37, C38, C30, C40, i.e. methyl, ethyl, propyl, and so on). And those skilled in the art can understand that in some specific structures, when an alkyl group is clearly represented as a linking group, the alkyl group represents a connected alkylene group, therefore, "alkylene "You can also refer to the relevant definition in the above-mentioned aliphatic hydrocarbon group, for example, the number of carbon atoms of the alkylene group can be C1, C2, C3, C4, C5, C6, C6, C7, C8, C9, C10 (that is, the alkylene group Alkyl can be methylene, ethylene, and so on).

The term "biocompatibility" refers to the interaction between the components of a composition and the body.

The term "active ingredient" refers to a drug used in the treatment of a disease. Therefore, active ingredients, drugs can be used alternatively. The term "active ingredient" or "drug" as used herein includes, but is not limited to, pharmaceutically active substances of local or systemic action, which may be administered topically or by injection, such as subcutaneous, intradermal, intramuscular and intraarticular injections . At least one active ingredient is present in the sustained release drug delivery system of the present invention.

The term "amide type" used in the present invention refers to amide or caine local anesthetics, such as bupivacaine, levobupivacaine, ropivacaine, mepivacaine, lidocaine and the like. Amide local anesthetics are generally composed of a lipophilic part and a hydrophilic part. The lipophilic part can be an aromatic hydrocarbon or an aromatic heterocycle, and the benzene ring has the strongest effect. The introduction of electron-donating groups such as amino groups on the benzene ring can enhance the activity. The hydrophilic part is generally secondary amine, tertiary amine or pyrrolidine, piperidine, morpholine, etc., and tertiary amine is the most common. The pKa is generally between 7.5 and 7.9, and it is ionic under physiological conditions.

The abbreviations used in the present invention have the following definitions: SPC is soybean phosphatidylcholine (soybean phosphatidylcholine), EPC is egg yolk phosphatidylcholine (egg yolk phospholipid), HSPC is hydrogenated soybean phosphatidylcholine, DLPC is dilauroylphosphatidylcholine Choline, DMPC is dimyristoylphosphatidylcholine, DPPC is dipalmitoylphosphatidylcholine, DSPC is distearoylphosphatidylcholine, DEPC is dierucoylphosphatidylcholine, DOPC is dioleoylphosphatidylcholine Acylcholine (dioleoyl phosphatidylcholine), POPC is palmitoyl oleoyl phosphatidylcholine, BA is benzyl alcohol, NMP is N-methylpyrrolidone, DMSO is dimethyl sulfoxide, BUP is bupivacaine, ROP represents ropivacaine, MLX represents meloxicam, CHO represents cholesterol, PRX represents piroxicam, LBUP represents levobupivacaine, TAC represents triamcinolone acetonide, KTL represents ketorolac, CLD represents clonidine, EtOH represents none Water ethanol, BA represents benzyl alcohol, PEG200 represents polyethylene glycol 200, PEG400 represents polyethylene glycol 400, and PEG600 represents polyethylene glycol 600.

Beneficial effect

1) The present invention provides a sustained-release preparation composition, which is a high-viscosity liquid at normal temperature and can undergo phase transition at the site of administration. The selected auxiliary material components in the present invention have good biocompatibility. The present invention unexpectedly finds that by controlling the ratio of glycerin, slow-release carrier, and solvent system, the viscosity of the composition preparation can be significantly increased, making the pharmaceutical composition easier to infuse and administer, while staying in the body for a longer time, and improving the drug's sustained release. release effect.

2) The present invention further found that adding a suitable release modifier to the formulation system can further improve the viscosity of the system and improve the release performance of the active ingredient;

3) The composition of the present invention is less irritating and has good drug safety and tolerance.

4) The sustained-release preparation system provided by the present invention can achieve good release performance of active pharmaceutical ingredients and reduce the possibility of burst release.

5) The composition of the present invention is especially suitable for the development of pharmaceutical preparations with anesthesia and analgesic activity, and has more advantages compared to other sustained-release analgesic drug systems, such as continuous and stable release of analgesic active ingredients, not only can be injected It is suitable for stable and convenient local administration, with good tolerance of patients and few side effects.

Description of drawings

Figures 1-1 to 1-4 are the rheological results of compositions 3058, 3061, 3062, and 3064, respectively.

Figures 1-5 are viscosity-shear rate curves for compositions 3058, 3061, 3062, 3064.

Figure 2-1 shows the status of the administration sites of compositions 3075 and 3076 in rats at 24h, 48h, and 72h.

Figure 3-1 to Figure 3-2 are the plasma concentration-time curves of ropivacaine and bupivacaine, and the plasma concentration-time curves of meloxicam of compositions 3077 and 3078, respectively.

Figure 4-1 to Figure 4-2 are respectively the plasma concentration-time curves of ropivacaine and meloxicam of compositions 3079 and 3080.

Figure 5-1 to Figure 5-2 are respectively the plasma concentration-time curves of ropivacaine and meloxicam of the composition 3082.

Figure 6-1 to Figure 6-2 are the blood concentration-time curves of ropivacaine and meloxicam blood concentration-time curves of compositions 3079, 3080, and 3081, respectively.

Detailed ways

The technical solutions of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following examples are only for illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies realized based on the above contents of the present invention are covered within the scope of protection intended by the present invention.

Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

Source of experimental animals:

Example 1

Study on the Viscosity of Compositions by Different Types of Alcohols

Prepare the composition according to Table 1-1, dissolve SPC in BA under heating, add glycerin, propylene glycol, PEG200, PEG400, PEG600 respectively, heat and stir until a uniform solution is formed, and place it at room temperature to investigate the effect of different alcohols on the viscosity of the system Influence. No. 14 rotor was used to detect the viscosity of the composition at a rotational speed of 50 rpm, and the results are shown in Table 1-2.

Table 1-1 Composition Active Ingredients

Table 1-2 Composition solution state and viscosity

The present invention unexpectedly finds that adding glycerol to the phospholipid solution can significantly increase the viscosity of the composition, while propylene glycol and polyethylene glycol with different molecular weights do not significantly increase the viscosity of the composition.

Example 2

Study on the Ratio of Glycerin/Organic Solvent/Slow-release Carrier to the Viscosity of the Composition

Prepare the composition according to Table 2-1 and 2-2, dissolve SPC in solvents of different types and proportions under heating, add glycerin, heat and stir until a uniform solution is formed, and after standing at room temperature, investigate the ratio of auxiliary materials in the composition to the viscosity of the system Impact.

Table 2-1 Viscosity detection results of compositions containing different solvents

Table 2-2 Viscosity detection results of compositions containing different solvents

Example 3

Composition Uniformity Studies

Take the compositions of different viscosities in Table 2-1 and 2-2 in PE tubes, centrifuge at 9000rpm for 15min, and observe the state of the solution after centrifugation. The results are shown in Table 3-1 and Table 3-2.

Table 3-1 Composition uniformity results of different solvents (benzyl alcohol)

Table 3-2 Composition uniformity results of different solvents (absolute ethanol)

It can be seen from the results that the samples at different viscosities were in a homogeneous state without delamination after high-speed centrifugation, indicating good physical stability.

Example 4

Rheology study

Compositions were prepared according to Table 4-1, and rheological studies were carried out. Rheometer model: TA DHR-1, sample volume: 1mL. Measurement mode: Oscillation mode: time sweep, fixed Strain 0.5%, frequency 1Hz; Oscillation mode: frequency sweep, fixed Strain 0.5%, frequency sweep range 0.1-100rad/s.

Table 4-1 Composition ingredients

In rheology, when the storage modulus (G') is greater than the loss modulus (G"), the sample exhibits gel properties, and when the storage modulus (G') is less than the loss modulus (G"), the sample exhibits gel properties. Solution properties. As shown in Figures 1-1 to 1-4, the compositions of the present invention all exhibit solution properties.

Figure 1-5 is the viscosity-shear rate curve of the composition in Table 4-1. It can be seen that the viscosity of the composition increases with the increase of the amount of glycerin, and the viscosity of the composition can be adjusted by adding a regulator. In addition, the composition exhibits a phenomenon of shear thinning as the shear rate increases.

Example 5

Pharmaceutical compositions containing different proportions of glycerin

Prepare the composition according to Table 5-1, dissolve the SPC and the active ingredient in the organic solvent under heating, add different proportions of glycerin, and heat and stir to form a uniform solution.

Table 5-1 Composition ingredients

Example 6

Drug release from pharmaceutical compositions with different ratios of glycerol

The release of ropivacaine from the composition of Example 5 was determined by adding 100 mg of the pharmaceutical composition from Example 5 to a dialysis bag and placing it in a tube containing 200 mL of phosphate buffer. Shake at 37°C, and take 1 mL of phosphate buffer solution from the tube at 24h, 48h, and 72h respectively. The concentrations of ropivacaine mesylate and meloxicam in each sample were determined by HPLC. The results are shown in Table 6-1 below.

Table 6-1 Release of ropivacaine mesylate and meloxicam from the composition

Example 7

Pharmaceutical compositions containing different ratios of release modifiers

Prepare the composition according to Table 7-1, dissolve SPC, DPPC and the active ingredient in the organic solvent under heating, add glycerin, heat and stir, and a uniform solution can be formed.

Table 7-1 Composition ingredients

Example 8

Drug release from pharmaceutical compositions with different ratios of release modifiers

The release of ropivacaine from the composition of Example 7 was determined by adding 100 mg of the pharmaceutical composition from Example 7 into a dialysis bag and placing it in a tube containing 200 mL of phosphate buffer. Shake at 37°C, and take 1 mL of phosphate buffer solution from the tube at 24h, 48h, and 72h respectively. The concentrations of ropivacaine mesylate and meloxicam in each sample were determined by HPLC. The results are shown in Table 8-1 below.

Table 8-1 Release of ropivacaine mesylate and meloxicam from the composition

Example 9

Pharmaceutical compositions containing different active ingredients

Prepare the composition according to Table 9-1, dissolve the SPC and the active ingredient in the organic solvent under heating, add glycerin, and heat and stir to form a uniform solution.

Table 9-1 Composition ingredients

serial number

glycerin

SPC

BA

Hydrochloric acid ROP

ROP methanesulfonate

Hydrochloric acid BUP

MLX

PRX

NMP

the	wt%	wt%	wt%	wt%	wt%	wt%	wt%	wt%	wt%
3066	8	67.6	16.9	6	0	0	0.15	0	1.35
3067	8	67	16.75	0	6.75	0	0.15	0	1.35
3068	8	67.6	16.9	0	0	6	0.15	0	1.35
3069	8	67.6	16.9	0	6	0	0	0.15	1.35

Example 10

Pharmaceutical compositions containing different active ingredients

Prepare the composition according to Table 10-1, dissolve the SPC and the active ingredient in the organic solvent under heating, add glycerin, and heat and stir to form a uniform solution.

Table 10-1 Composition ingredients

Example 11

Pharmaceutical composition containing different antioxidants

Prepare the composition according to Table 11-1, dissolve the SPC and the active ingredient in the organic solvent under heating, add glycerin, and heat and stir to form a uniform solution.

Table 11-1 Compositions containing different antioxidants

Example 12

Stability of Pharmaceutical Compositions

Prepare the composition according to Table 12-1, dissolve the SPC and the active ingredient in the organic solvent under heating, add glycerin, and heat and stir to form a uniform solution. Place the samples at 60°C and 40°C to investigate the changes of related substances, the results are shown in Table 12-2.

Table 12-1 Compositions containing different antioxidants

Table 12-2 Composition Stability

From the results in Table 12-2, it can be known that the pharmaceutical composition has no significant increase in related substances under the conditions of 60°C and 40°C, and the chemical stability is good.

Example 13

In vivo administration of pharmaceutical compositions

Prepare the composition according to Table 13-1, remove the hair on the outside of the right hind leg of the rat, and administer 0.2 mL of the composition subcutaneously to each rat (the dosage is 100 mg/kg, containing 20 mg according to ROP), at 24h, 48h and Killed by dislocation at 72 hours, opened the administration site, and observed the shape of the preparation at the administration site. The results are shown in Figure 2-1. Composition 3075 and Composition 3076 were still able to see the reservoir after 72h.

Table 13-1 Composition ingredients

Example 14

In vivo administration of pharmaceutical compositions

In vivo pharmacokinetic studies in dogs are as follows. Beagle dogs with a weight of about 10 kg were fasted for more than 12 hours (take off the food box for feeding) before the experiment, drink water freely, and give food 4 hours after the administration. Each group was administered by subcutaneous injection, and the sample information is shown in Table 14-1. Every Beagle dog accepts injection twice, each 50mg, and each group animal takes 0 hour before administration, after administration 0.5, 1, 2, 3, 6, 8, 12, 24, 36, 48, At 60, 72, and 96 hours, about 0.5 mL of blood samples were collected into EDTA-2K+ anticoagulated blood collection tubes. The whole blood was centrifuged at 8000 rpm for 5 minutes to collect plasma, and then the drug concentration in the plasma samples was detected by LC-MS/MS.

Table 14-1 Composition ingredients

The plasma concentration-time curves of compositions 3077 and 3078 are shown in Figure 3-1 and Figure 3-2.

Example 15

In vivo administration of pharmaceutical compositions

In vivo pharmacokinetic studies in dogs are as follows. Beagle dogs with a weight of about 10 kg were fasted for more than 12 hours (take off the food box for feeding) before the experiment, drink water freely, and give food 4 hours after the administration. Each group was administered by subcutaneous injection, and the sample information is shown in Table 15-1. Every Beagle dog accepts injection twice, each 50mg, and each group animal takes 0 hour before administration, after administration 0.5, 1, 2, 3, 6, 8, 12, 24, 36, 48, At 60, 72, and 96 hours, about 0.5 mL of blood samples were collected into EDTA-2K+ anticoagulated blood collection tubes. The whole blood was centrifuged at 8000 rpm for 5 minutes to collect plasma, and then the drug concentration in the plasma samples was detected by LC-MS/MS.

Table 15-1 Composition ingredients

The plasma concentration-time curves of compositions 3079 and 3080 are shown in Figure 4-1 and Figure 4-2.

Example 16

In vivo administration of pharmaceutical compositions

In vivo pharmacokinetic studies in dogs are as follows. Beagle dogs with a weight of about 10 kg were fasted for more than 12 hours (take off the food box for feeding) before the experiment, drink water freely, and give food 4 hours after the administration. Each group was administered by subcutaneous injection, and the sample information is shown in Table 16-1. Every Beagle dog accepts injection twice, each 50mg, and each group animal takes 0 hour before administration, after administration 0.5, 1, 2, 3, 6, 8, 12, 24, 36, 48, At 60, 72, and 96 hours, about 0.5 mL of blood samples were collected into EDTA-2K+ anticoagulated blood collection tubes. The whole blood was centrifuged at 8000 rpm for 5 minutes to collect plasma, and then the drug concentration in the plasma samples was detected by LC-MS/MS.

Table 16-1 Composition ingredients

The plasma concentration-time curves of composition 3082 are shown in Figure 5-1 and Figure 5-2.

Example 17

In vivo administration of pharmaceutical compositions

The pharmacokinetic study in rats is as follows. Animals with a weight of about 180-200 g were randomly grouped and uniquely identified by tail numbers. Inject subcutaneously on the back of the neck of rats, and the administration volume is fixed at 0.2mL/animal. Blood samples were collected 0 h before administration and approximately 0.5, 1, 2, 3, 6, 8, 10, 24, 34, 48, 72 and 96 h after administration into K2EDTA anticoagulant tubes, temporarily stored on ice until centrifuged. Plasma needs to be centrifuged within 60 minutes after blood collection (under the condition of 2-8°C, centrifuge at 8000rpm for 5min). MS detection.

Table 17-1 Composition ingredients

The plasma concentration-time curves of compositions 3079, 3080, and 3081 are shown in Figure 6-1 and Figure 6-2.

Exemplary embodiments of the present invention have been described above. However, the scope of protection of the present invention is not limited to the above-mentioned embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims (10)

1. A pharmaceutical composition comprising the following components:

   a. pharmaceutical active ingredient, the pharmaceutical active ingredient is selected from ropivacaine hydrochloride, ropivacaine mesylate, bupivacaine hydrochloride, levobupivacaine hydrochloride, meloxicam, celecoxib, One or a combination of ketorolac and triamcinolone acetonide;

   b. Glycerin;

   c. slow-release carrier, the slow-release carrier is selected from one or more of the compounds of formula I or formula II, and the compound of formula I is

   

   Wherein, Rs is selected from H,

   

   

   Each R ₁ , R ₂ is the same or different, independently selected from saturated or unsaturated aliphatic hydrocarbon groups; each R ₃ , R ₄ , R ₅ is the same or different, independently selected from H or alkyl; L is selected from Alkylene; The compound of formula II is

   

   Wherein, R is selected from alkyl;

   d. At least one pharmaceutically acceptable solvent.
2. The pharmaceutical composition according to claim 1, characterized in that,

   In the formula I, each R ₁ and R ₂ are the same or different, and are independently selected from C _10-30 saturated or unsaturated aliphatic hydrocarbon groups, such as C _13-21 alkyl groups; each R ₃ , R ₄ , R ₅ are the same or different, independently selected from H or C _1-10 alkyl, for example independently selected from H, methyl, ethyl; said L is selected from C _1-10 alkylene, preferably, L selected from C _1-6 alkylene groups, such as methylene and ethylene; in the compound shown in formula II, R is selected from C _1-10 alkyl groups, such as C _8-10 alkyl groups.
3. The pharmaceutical composition according to claim 1 or 2, characterized in that,

   The c-component slow-release carrier is selected from HSPC (hydrogenated soybean lecithin), DMPC (dimyristoyl phosphatidyl choline), DPPC (dipalmitoyl phosphatidyl choline), DSPC (distearoyl phosphatidyl choline), ), DLPC (dilauroylphosphatidylcholine), SPC soybean phosphatidylcholine (soybean phosphatidylcholine), EPC (egg yolk phospholipid), rapeseed phosphatidylcholine, sunflower phosphatidylcholine, DEPC (dierucoyl phosphatidylcholine), DOPC (two oil Acyl Lecithin), POPC (Palmitoyl Oleoyl Lecithin), Sphingomyelin, Distearoyl Phosphatidic Acid (DSPA), Dioleoyl Phosphatidylethanolamine (DOPE), Dipalmitoyl Phosphatidic Acid (DPPA), Myristic Acyl lysophospholipid (M-lysoPC), palmitoyl lysophospholipid (P-lysoPC), 1-stearoyl-lysophosphatidylcholine (S-lysoPC), dipalmitoylphosphatidylethanolamine (DPPE), distearoyl Phosphatidylethanolamine (DSPE), Dioleoylphosphatidylglycerol (DOPG), Dimyristoylphosphatidylethanolamine (DMPE), Dimyristoylphosphatidylglycerol (DMPG), Dipalmitoylphosphatidylglycerol (DPPG), 1 - Palmitoyl-2-oleoylphosphatidylglycerol (POPG), distearoylphosphatidylglycerol (DSPG), dipalmitoylphosphatidylserine (DPPS), phosphatidylinositol (PI), cholesterol (CHO) one or more of.
4. The pharmaceutical composition according to any one of claims 1-3, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable release modifier; and/or the pharmaceutical composition may further comprise one or Various antioxidants;
5. The pharmaceutical composition according to any one of claims 1-4, wherein the solvent is a non-aqueous solvent.
6. The pharmaceutical composition according to claim 4, wherein the pharmaceutically acceptable release regulator is selected from one or more of sterols, saturated phospholipids and other surfactants; preferably, the sterols is cholesterol; the saturated phospholipids are selected from hydrogenated soybean phospholipids (HSPC), dilauroyl lecithin (DLPC), dimyristoyl lecithin (DMPC), distearoyl phosphatidylcholine (DSPC), dipalmitoyl Lecithin etc. (DPPC); The surfactant is selected from the group consisting of polyoxyl 40 stearate, caprylic capric macrogol glyceride, lauroyl polyoxyethylene glyceride, stearyl polyoxyethylene glyceride, Oleoyl polyoxyethylene glyceride, vitamin E macrogol succinate, poloxamer, polysorbate, macrogol-12-hydroxystearate, propylene glycol monocaprylate, glyceryl dioleate ester, glyceryl monooleate; said antioxidant is selected from vitamin C (ascorbic acid), cysteine hydrochloride, vitamin E (tocopherol), ascorbyl palmitate, glutathione, alpha lipoic acid, sulfur substitute glycerin.
7. The pharmaceutical composition according to any one of claims 1-6, wherein the mass ratio of the glycerol to the slow-release carrier/pharmaceutically acceptable solvent is 1:0.1 to 1:99; the slow-release carrier The mass ratio of the pharmaceutically acceptable solvent is 1:0.1 to 1:10; the glycerin accounts for about 1% to about 95% (w/w) of the total composition; the slow-release carrier accounts for the total composition 3% to 90% (w/w); the pharmaceutically active ingredient accounts for 0.1% to 50.0% (w/w) of the total composition; the total amount of the solvent accounts for 5% to 50% of the total composition (w/w).
8. The preparation method of the pharmaceutical composition according to any one of claims 1-7, characterized in that it comprises the steps of:

   (a1) Mix the slow-release carrier and the pharmaceutically acceptable solvent, stir or shear under heating conditions to a clear and uniform mixed solution;

   (a2) adding at least one pharmaceutically active ingredient to the mixed solution, stirring or shearing under heating conditions to form a homogeneous mixture;

   (a3) adding glycerin to the mixed solution, stirring or shearing under heating conditions until a uniform solution is formed;

   Preferably, the mixing of the step (a1) also includes adding at least one pharmaceutically acceptable release regulator, for example, the step (a1) can be a slow-release carrier, a pharmaceutically acceptable solvent, glycerin and Release modifier mix.
9. A sustained-release preparation comprising the pharmaceutical composition according to any one of claims 1-7, wherein the preparation is administered as a depot preparation, preferably, the preparation is injectable or the preparation can be Local administration; more preferably, the preparation can be injected subcutaneously, around nerves, intramuscularly, perfused (directly applied to the wound, arterially perfused, rectally perfused), and can also be administered externally through the skin or through the mucous membrane.
10. The preparation according to claim 9, characterized in that, the preparation further comprises a packaging material filled with the preparation, and the packaging material is selected from one or more of the following: vials, prefilled syringes, cassettes bottle.

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